1886-LB: A Novel Antibody–Peptide Conjugate Targeting PCSK9,GLP-1R,GCGR,GIPR Improves Cardiovascular Risk Markers in Preclinical Study

Introduction and Objective: PCSK9 is a secreted protease that mediates low-density lipoprotein receptor (LDLR) degradation, thereby regulating plasma LDL-cholesterol levels. Glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR), and glucose-dependent insulinotropic polypeptide receptor (GIPR) are associated with metabolic regulation mechanisms including insulin secretion and energy expenditure. IBI3030 is a novel anti-PCSK9 antibody conjugated with GLP-1R/GCGR/GIPR agonist peptide, potentially offering enhanced therapeutic benefits for cardiovascular disease patients. Methods: LDL-cholesterol uptake activity was assessed in HepG2 cells. Agonist potencies for GLP-1R/GCGR/GIPR were evaluated through cAMP accumulation assays. The hPCSK9 knock-in mice, AAV8-hPCSK9-induced ob/ob mice, and rats) were studied with monitoring of body weight changes and oral glucose tolerance test performance. Metabolic parameters including LDL-cholesterol, total cholesterol, and glucose were measured. NHP studies assessed toxicity and efficacy through body weight monitoring and cardiovascular biomarker analysis. Results: IBI3030 demonstrated comparable LDL-cholesterol uptake enhancement to commercial PCSK9 antibodies. The conjugate exhibited potent triagonist activity in cAMP assays. Treatment significantly reduced LDL-cholesterol (p<0.01 vs baseline) and improved glucose tolerance across all models. Significant body weight reduction was observed with preserved insulin sensitivity. IBI3030 showed favorable tolerability up to 50 mg/kg in NHPs, with concurrent improvements in both GLP-1-associated (body weight, food consumption) and PCSK9-related pharmacodynamic markers. Conclusion: IBI3030 demonstrated concurrent improvements in cholesterol homeostasis, glycemic control, and obesity parameters across preclinical models. This novel bioconjugate shows potential for delivering enhanced clinical benefits in cardiovascular disease management. Disclosure D. Ren: None. Y. Li: Employee; Innovent Biologics.